Controlled release oxycodone compositions

ABSTRACT

A method for substantially reducing the range in daily dosages required to control pain in approximately 90% of patients is disclosed whereby an oral solid controlled release dosage formulation having from about 10 to about 40 mg of oxycodone or a salt thereof is administered to a patient. The formulation provides a mean maximum plasma concentration of oxycodone from about 6 to about 60 ng/ml from a mean of about 2 to about 4.5 hours after administration, and a mean minimum plasma concentration from about 3 to about 30 ng/ml from about 10 to about 14 hours after repeated “g12h” (i.e., every 12 hour) administration through steady-state conditions. Another embodiment is directed to a method for substantially reducing the range in daily dosages required to control pain in substantially all patients by administering an oral solid controlled release dosage formulation comprising up to about 160 mg of oxycodone or a salt thereof, such that a mean maximum plasma concentration of oxycodone up to about 240 ng/ml from a mean of up to about 2 to about 4.5 hours after administration, and a mean minimum plasma concentration up to about 120 ng/ml from about 10 to about 1.4 hours after repeated “q12h” (i.e., every 12 hour) administration through steady-state conditions are achieved. Controlled release oxycodone formulations for achieving the above are also disclosed.

[0001] This application is a continuation of Ser. No. 08/081,302, filedJun. 18, 1993, which is a continuation-in-part of Ser. No. 07/800,549,filed Nov. 27, 1991, now U.S. Pat. No. 5,266,331, hereby incorporated byreference.

BACKGROUND OF THE INVENTION

[0002] Surveys of daily dosages of opioid analgesics required to controlpain suggest that an approximately eight-fold range in daily dosages isrequired to control pain in approximately 90% of patients. Thisextraordinary wide range in the appropriate dosage makes the titrationprocess particularly time consuming and resource consuming, as well asleaving the patient without acceptable pain control for an unacceptablylong duration.

[0003] In the management of pain with opioid analgesics, it has beencommonly observed and reported that there is considerableinter-individual variation in the response to a given dose of a givendrug, and, therefore, considerable variability among patients in thedosage of opioid analgesic required to control pain without unacceptableside effects. This necessitates considerable effort on the part ofclinicians in establishing the appropriate dose in an individual patientthrough the time consuming process of titration, which requires carefulassessment of both therapeutic and side effects and dosage adjustmentsover a period of days and sometimes longer before the appropriate dosageis determined. The American Pain Society's 3rd Edition of Principles ofAnalgesic Use in the Treatment of Acute Pain and Cancer Pain explainsthat one should “be aware that the optimal analgesic dose varies widelyamong patients. Studies have shown that in all age groups, there isenormous variability in doses of opioids required to provide relief,even among opioid naive patients with identical surgical lesions. Thisgreat variability underscores the need to write analgesic orders thatinclude provision for supplementary doses, and to use intravenousboluses and infusions to provide rapid relief of severe pain. Give eachanalgesic an adequate trial by dose titration before switching toanother drug.”

[0004] An opioid analgesic treatment which acceptably controls pain overa substantially narrower daily dosage range would, therefore,substantially improve the efficiency and quality of pain management.

[0005] It has previously been known in the art that controlled releasecompositions of opioid analgesics such as morphine, hydromorphone orsalts thereof could be prepared in a suitable matrix. For example, U.S.Pat. No. 4,990,341 (Goldie), also assigned to the assignee of thepresent invention, describes hydromorphone compositions wherein thedissolution rate in vitro of the dosage form, when measured by the USPPaddle Method at 100 rpm in 900 ml aqueous buffer (pH between 1.6 and7.2) at 37° C., is between 12.5 and 42.5% (by wt) hydromorphone releasedafter 1 hour, between 25 and 55% (by wt) released after 2 hours, between45 and 75% (by wt) released after 4 hours and between 55 and 85% (by wt)released after 6 hours.

SUMMARY OF THE INVENTION

[0006] It is an object of the present invention to provide a method forsubstantially improving the efficiency and quality of pain management.

[0007] It is another object of the present invention to provide anopioid analgesic formulation which substantially improves the efficiencyand quality of pain management.

[0008] It is another object of the present invention to provide a methodand formulation(s) which substantially reduce the approximatelyeight-fold range in daily dosages required to control pain inapproximately 90% of patients.

[0009] It is another object of the present invention to provide a methodand formulation(s) which substantially reduce the variability in dailydosages and formulation requirements necessary to control pain insubstantially all patients.

[0010] It is yet another object of the present invention to provide amethod for substantially reducing the time and resources need to titratepatients requiring pain relief on opioid analgesics.

[0011] It is yet another object of the present invention to providecontrolled release opioid formulations which have substantially lessinter-individual variation with regard to the dose of opioid analgesicrequired to control pain without unacceptable side effects.

[0012] The above objects and others are attained by virtue of thepresent invention, which is related to a solid controlled release oraldosage form, the dosage form comprising from about 10 to about 40 mg ofoxycodone or a salt thereof in a matrix wherein the dissolution rate invitro of the dosage form, when measured by the USP Paddle Method at 100rpm in 900 ml aqueous buffer (pH between, 1.6 and 7.2) at 37° C. isbetween 12.5 and 4.2.5% (by wt) oxycodone released after 1 hour, between25 and 56% (by wt) oxycodone released after 2 hours, between 45 and 75%(by wt) oxycodone released after 4 hours and between 55 and 85% (by wt)oxycodone released after 6 hours, the in vitro release rate beingsubstantially independent of pH, such that the peak plasma level ofoxycodone obtained in vivo occurs between 2 and 4.5 hours afteradministration of the dosage form.

[0013] USP Paddle Method is the Paddle Method described, e.g., in U.S.Pharmacopoeia XXII (1990).

[0014] In the present specification, “substantially independent of pH”means that the difference, at any, given time, between the amount ofoxycodone released at, e.g., pH 1.6, and the amount released at anyother pH, e.g., pH 7.2 (when measured in vitro using the USP PaddleMethod at 100 rpm in 900 ml aqueous buffer), is 10% (by weight) or less.The amounts released being, in all cases, a mean of at least threeexperiments.

[0015] The present invention is further related to a method forsubstantially reducing the range in daily dosages required to controlpain in approximately 90% of patients, comprising administering an oralsolid controlled release dosage formulation comprising from about 10 toabout 40 mg of oxycodone or a salt thereof, said formulation providing amean maximum plasma concentration of oxycodone from about 6 to about 60ng/ml from a mean of about 2 to about 4.5 hours after administration,and a mean minimum plasma concentration from about 3 to about 30 ng/mlfrom a mean of about 10 to about 14 hours after repeated “q12h” (i.e.,every 12 hour) administration through steady-state conditions.

[0016] The present invention is further related to a method forsubstantially reducing the range in daily dosages required to controlpain in substantially all patients, comprising administering an oralsolid controlled release dosage formulation comprising up to about 160mg of oxycodone or a salt thereof, said formulation providing a meanmaximum plasma concentration of oxycodone up to about 240 ng/ml from amean of up to about 2 to about 4.5 hours after administration, and amean minimum plasma concentration up to about 120 ng/ml from a mean ofabout 10 to about 14 hours after repeated “q12h” (i.e., every 12 hour)administration through steady-state conditions.

[0017] The present invention is further related to controlled releaseoxycodone formulations comprising from about 10 to about 40 mg oxycodoneor a salt thereof, said formulations providing a mean maximum plasmaconcentration of oxycodone from about 6 to about 60 ng/ml from a mean ofabout 2 to about 4.5 hours after administration, and a mean minimumplasma concentration from about 3 to about 30 ng/ml from about 10 toabout 14 hours after repeated q12h administration through steady-stateconditions.

[0018] The present invention is further related to con trolled releaseoxycodone formulations comprising up to about 160 mg oxycodone or a saltthereof, said formulations providing a mean maximum plasma concentrationof oxycodone up to about 240 ng/ml from a mean of about 2 to about 4.5hours after administration, and a mean minimum plasma concentration upto about 120 ng/ml from about 10 to about 14 hours after repeated q12hadministration through steady-state conditions.

BRIEF DESCRIPTION OF THE DRAWINGS

[0019] The following drawings are illustrative of embodiments of theinvention and are not meant to limit the scope of the invention asencompassed by the claims.

[0020] FIGS. 1-4 are graphs showing the time-effect curves for painintensity differences and pain relief for Example 17;

[0021]FIG. 5 is a graph-showing the mean plasma oxycodone concentrationfor a 10 mg controlled release oxycodone formulation prepared inaccordance with the present invention and a study reference standard.

DETAILED DESCRIPTION

[0022] It has now been surprisingly discovered that the presentlyclaimed controlled release oxycodone formulations acceptably controlpain over a substantially narrower, approximately four-fold (10 to 40 mgevery 12 hours—around-the-clock dosing) in approximately 90% ofpatients. This is in sharp contrast to the approximately eight-foldrange required for approximately 90% of patients for opioid analgesicsin general.

[0023] The use of from about 10 mg to about 40 mg of 12 hourly doses ofcontrolled-release oxycodone to control pain in approximately 90% ofpatients relative to a wider dosage range of other mμ-agonistanalgesics, indicated for moderate to severe pain, is an example of theunique characteristics of the present invention. It should also beappreciated that the remaining 10% of patients would also besuccessfully managed with. 12-hourly controlled-release oxycodone over arelatively narrower dosage range than with the use of other similaranalgesics. Substantially all of those remaining 10% of patients notmanaged with controlled release oxycodone, 10 mg to 40 mg every 12hours, would be managed using dosages of greater than 40 mg every 12hours through 160 mg every 12 hours utilizing any one of a number ormultiples of formulation strengths such as 10, 20, 40, 80 and 160 mgunit dosages or combinations thereof. In contrast, the use of othersimilar analgesics such as morphine would require a wider range ofdosages to manage the remaining 10% of patients. For example, dailydosages of oral morphine equivalents in the range of 1 gram to more than20 grams have been observed. Similarly, wide dosage ranges of oralhydromorphone would also be required.

[0024] Morphine, which is considered to be the prototypic opioidanalgesic, has been formulated into a 12 hour controlled-releaseformulations (i.e., MS Contin® tablets, commercially available fromPurdue Pharma, L.P.). Despite the fact that both controlled-releaseoxycodone and controlled release morphine administered every 12 hoursaround-the-clock possess qualitatively comparable clinicalpharmacokinetic characteristics, the oxycodone formulations of thepresently claimed invention can be used over approximately ½ the dosagerange as compared to commercially available controlled release morphineformulations (such as MS Contin®) to control 90% of patients withsignificant pain.

[0025] Repeated dose studies with the controlled release oxycodoneformulations administered every 12 hours in comparison with immediaterelease oral oxycodone administered every 6 hours at the same totaldaily dose result in comparable extent of absorption, as well ascomparable maximum and minimum concentrations. The time of maximumconcentration occurs at approximately 2-4.5 hours after oraladministration with the controlled-release product as compared toapproximately 1 hour with the immediate release product. Similarrepeated dose studies with MS Contin® tablets as compared to immediaterelease morphine provide for comparable relative results as with thecontrolled release oxycodone formulations of the present invention.

[0026] There exists no substantial deviation from parallelism of thedose-response curves for oxycodone either in the forms of the controlledrelease oxycodone formulations of the present invention, immediaterelease oral oxycodone or parenteral oxycodone in comparison with oraland parenteral opioids with which oxycodone has been compared in termsof dose-response studies and relative analgesic potency assays. Beaver,et al., “Analgesic Studies of Codeine and Oxycodone in Patients withCancer. II. Comparisons of Intramuscular Oxycodone with IntramuscularMorphine and Codeine”, J. Pharmacol. and Exp. Ther., Vol. 207, No. 1,pp. 101-108, reported comparable dose-response slopes for parenteraloxycodone as compared to parenteral morphine and comparabledose-response slopes for oral as compared to parenteral oxycodone.

[0027] A review of dose-response studies and relative analgesic assaysof mu-agonist opioid analgesics, which include oxycodone, morphine,hydromorphone, levorphanol, methadone, meperidine, heroin, all indicateno significant deviation from parallelism in their dose responserelationships. This is so well established that it has become anunderlining principal providing for establishing relative analgesicpotency factors and dose ratios which are commonly utilized whenconverting patients from one mμ-agonist analgesic to another regardlessof the dosage of the former. Unless the dose-response curves areparallel, conversion factors would not be valid across the wide range ofdosages involved when substituting one drug for another.

[0028] The clinical significance provided by the controlled releaseoxycodone formulations of the present invention at a dosage range fromabout 10 to about 40 mg every 12 hours for acceptable pain management inapproximately 90% of patients with moderate to severe pain, as comparedto other opioid analgesics requiring approximately twice the dosagerange provides for the most efficient and humane method of managing painrequiring repeated dosing. The expertise and time of physicians andnurses, as well as the duration of unacceptable pain patients mustendure during the opioid analgesic titration process is substantiallyreduced through the efficiency of the controlled release oxycodoneformulations of the present invention.

[0029] It is further clinically significant that a dose of about 80, mgcontrolled release oxycodone administered every 12 hours will provideacceptable pain relief management in, e.g., approximately 95% ofpatients with moderate to severe pain, and that about 160 mg controlledrelease oxycodone administered every 12 hours will provide acceptablepain relief management in, e.g.; approximately all patients withmoderate to severe pain.

[0030] In order to obtain a controlled release drug dosage form havingat least a 12 hour therapeutic effect, it is usual in the pharmaceuticalart to produce a formulation that gives a peak plasma level of the drugbetween about 4-8 hours after administration (in a single dose study).The present inventors have surprisingly found that, in the case ofoxycodone, a peak plasma level at between. 2-4.5-hours afteradministration gives at least 12 hours pain relief and, mostsurprisingly, that the pain relief obtained with such a formulation isgreater than that achieved with formulations giving peak plasma levels(of oxycodone) in the normal period of up to 2 hours afteradministration.

[0031] A further advantage of the present composition, which releasesoxycodone at a rate that is substantially independent of pH, is that itavoids dose dumping upon oral administration. In other words, theoxycodone is released evenly throughout the gastrointestinal tract.

[0032] The present oral dosage form may be presented as, for example,granules, spheroids or pellets in a capsule or in any other suitablesolid form. Preferably, however, the oral dosage form is a tablet.

[0033] The present oral dosage form preferably contains between 1 and500 mg, most especially between 10 and 160 mg, of oxycodonehydrochloride. Alternatively, the dosage form may contain molarequivalent amounts of other oxycodone salts or of the oxycodone base.

[0034] The present matrix may be any matrix that affords in vitrodissolution rates of oxycodone within the narrow ranges required andthat releases the oxycodone in a pH independent manner. Preferably thematrix is a controlled release matrix, although normal release-matriceshaving a coating that controls the release of the drug may be used.Suitable materials for inclusion in a controlled release matrix are

[0035] (a) Hydrophilic polymers, such as gums, cellulose ethers, acrylicresins and protein derived materials. Of these polymers, the celluloseethers, especially hydroxyalkylcelluloses and carboxyalkylcelluloses,are preferred. The oral dosage form may contain between 1% and 80% (byweight) of at least one hydrophilic or hydrophobic polymer.

[0036] (b) Digestible, long chain (C₈-C₅₀, especially C₁₂-C₄₀),substituted or unsubstituted hydrocarbons, such as fatty acids, fattyalcohols, glyceryl esters of fatty acids, mineral and vegetable oils andwaxes. Hydrocarbons having a melting point of between 25° and 90° C. arepreferred. Of these long chain hydrocarbon materials, fatty (aliphatic)alcohols are preferred. The oral dosage form may contain up to 60% (byweight) of at least one digestible, long chain hydrocarbon.

[0037] (c) Polyalkylene glycols. The oral dosage form may contain up to606 (by weight) of at least one polyalkylene glycol.

[0038] One particular suitable matrix comprises at least one watersoluble hydroxyalkyl cellulose, at least one C₁₂-C₃₆, preferablyC₁₄-C₂₂, aliphatic alcohol and, optionally, at least one polyalkyleneglycol. The at least one hydroxyalkyl cellulose is preferably a hydroxy(C₁ to C₆) alkyl cellulose, such as hydroxypropylcellulose,hydroxypropylmethylcellulose and, especially, hydroxyethyl cellulose.The amount of the at least one hydroxyalkyl cellulose in the presentoral dosage form will be determined, inter alia, by the precise rate ofoxycodone release required. Preferably however, the oral dosage formcontains between 5% and 25%, especially between 6.25% and 15% (by wt) ofthe at least one hydroxyalkyl cellulose.

[0039] The at least one aliphatic alcohol may be, for example, laurylalcohol, myristyl alcohol or stearyl alcohol. In particularly preferredembodiments of the present oral dosage form, however, the at least onealiphatic alcohol is cetyl alcohol or cetostearyl alcohol. The amount ofthe at least one aliphatic alcohol in the present oral dosage form willbe determined, as above, by the precise rate of oxycodone releaserequired. It will also depend on whether at least one polyalkyleneglycol is present in or absent from the oral dosage form. In the absenceof at least one polyalkylene glycol, the oral dosage form preferablycontains between 20% and 50% (by wt) of the at least one aliphaticalcohol. When at least one polyalkylene glycol is present in the oraldosage form, then the combined weight of the at least one aliphaticalcohol and the at least one polyalkylene glycol preferably constitutesbetween 20% and 50% (by wt) of the total dosage.

[0040] In one preferred embodiment, the controlled release compositioncomprises from about 5 to about 25% acrylic resin and from about 8 toabout 40% by weight aliphatic alcohol by weight of the total dosageform. A particularly preferred acrylic resin comprises Eudragit® RS PM,commercially available from Rohm Pharma.

[0041] In the present preferred dosage form, the ratio of, e.g., the atleast one hydroxyalkyl cellulose or acrylic resin to the at least onealiphatic alcohol/polyalkylene glycol determines, to a considerableextent, the release rate of the oxycodone from the formulation. A ratioof, the at least one hydroxyalkyl cellulose to the at least onealiphatic alcohol/polyalkylene glycol of between 1:2 and 1:4 ispreferred, with a ratio of between 1:3 and 1:4 being particularlypreferred.

[0042] The at least one polyalkylene glycol may be, for example,polypropylene glycol or, which is preferred, polyethylene glycol. Thenumber average molecular weight of the at least one polyalkylene glycolis preferred between 1000 and 15000 especially between 1500 and 12000.

[0043] Another suitable controlled release matrix would comprise analkylcellulose (especially ethyl cellulose), a C₁₂ to C₁₆ aliphaticalcohol and, optionally, a polyalkylene glycol.

[0044] In addition to the above ingredients, a controlled release matrixmay also contain suitable quantities of other materials, e.g. diluents,lubricants, binders, granulating aids, colorants, flavorants andglidants that are conventional in the pharmaceutical art.

[0045] As an alternative to a controlled release matrix, the presentmatrix may be a normal release matrix having a coat that controls therelease of the drug. In particularly preferred embodiments of thisaspect of the invention, the present dosage form comprises film coatedspheroids containing active ingredient and a non-water solublespheronising agent. The term spheroid is known in the pharmaceutical artand means a spherical granule having a diameter of between 0.5 mm and2.5 mm especially between 0.5 mm and 2 mm.

[0046] The spheronising agent may be any pharmaceutically acceptablematerial that, together with the active ingredient, can be spheronisedto form spheroids. Microcrystalline cellulose is preferred.

[0047] A suitable microcrystalline cellulose is, for example, thematerial sold as Avicel PH 101 (Trade Mark, FMC Corporation). Accordingto a preferred aspect of the present invention, the film coatedspheroids contain between 70% and 99% (by wt), especially between 80%and 95% (by wt), of the spheronising agent, especially microcrystallinecellulose.

[0048] In addition to the active ingredient and spheronising agent, thespheroids may also contain a binder. Suitable binders, such as lowviscosity, water soluble polymers, will be well known to those skilledin the pharmaceutical art. However, water soluble hydroxy lower alkylcellulose, such as hydroxy propyl cellulose, are preferred. Additionally(or alternatively) the spheroids may contain a water insoluble polymer,especially an acrylic polymer, an acrylic copolymer, such as amethacrylic acid-ethyl acrylate copolymer, or ethyl cellulose.

[0049] The spheroids are preferably film coated with a material thatpermits release of the oxycodone (or salt) at a controlled rate in anaqueous medium. The film coat is chosen so as to achieve, in combinationwith the other ingredients., the in-vitro release rate outlined above(between 12.5% and 42.5% (by wt) release after 1 hour, etc.).

[0050] The film coat will generally include a water insoluble materialsuch as

[0051] (a) a wax, either alone or in admixture with a fatty alcohol,

[0052] (b) shellac or zein,

[0053] (c) a water insoluble cellulose, especially ethyl cellulose,

[0054] (d) a polymethacrylate, especially Eudragit®.

[0055] Preferably, the film coat comprises a mixture of the waterinsoluble material and a water soluble material. The ratio of waterinsoluble to water soluble material is determined by, amongst otherfactors, the release rate required and the solubility characteristics ofthe materials selected.

[0056] The water soluble material may be, for example,polyvinylpyrrolidone or, which is preferred, a water soluble cellulose,especially hydroxypropylmethyl cellulose.

[0057] Suitable combinations of water insoluble and water solublematerials for the film coat include shellac and polyvinylpyrrolidone or,which is preferred, ethyl cellulose and hydroxypropylmethyl cellulose.

[0058] In order to facilitate the preparation of a solid, controlledrelease, oral dosage form according to this invention there is provided,in a further aspect of the present invention, a process for thepreparation of a solid, controlled release, oral dosage form accordingto the present invention comprising incorporating hydromorphone or asalt thereof in a controlled release matrix. Incorporation in the matrixmay be effected, for example, by

[0059] (a) forming granules comprising at least one water solublehydroxyalkyl cellulose and oxycodone or a oxycodone salt,

[0060] (b) mixing the hydroxyalkyl cellulose containing granules with atleast one C₁₂-C₃₆ aliphatic alcohol, and

[0061] (c) optionally, compressing and shaping the granules. Preferably,the granules are formed by wet granulating the hydroxyalkylcellulose/oxycodone with water. In a particularly preferred embodimentof this process, the amount of water added during the wet granulationstep is preferably between 1.5 and 5 times, especially between 1.75 and3.5 times, the dry weight of the oxycodone. The present solid,controlled release, oral dosage form may also be prepared, in the formof film coated spheroids, by

[0062] (a) blending a mixture comprising oxycodone or a oxycodone saltand a non-water soluble spheronising agent,

[0063] (b) extruding the blended mixture to give an extrudate,

[0064] (c) spheronising the extrudate until spheroids are formed, and

[0065] (d) coating the spheroids with a film coat.

[0066] The present solid, controlled release, oral dosage form andprocesses for its preparation will now be described by way of exampleonly.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0067] The following examples illustrate various aspects of the presentinvention. They are not meant to be construed to limit the claims in anymanner whatsoever.

EXAMPLE 1 Controlled Release Oxycodone HCl 30 ma Tablets—AqueousManufacture

[0068] The required quantities of oxycodone hydrochloride, spray-driedlactose, and Eudragit® RS PM are transferred into an appropriate-sizemixer, and mixed for approximately 5 minutes. While the powders aremixing, the mixture is granulated with enough water to produce a moistgranular mass. The granules are then dried in a fluid-bed dryer at 60°C., and then passed through an 8-mesh screen. Thereafter, the granulesare redried and pushed through a 12-mesh screen. The required quantityof stearyl alcohol is melted at approximately 6.0-70° C., and while thegranules are mixing, the melted stearyl alcohol is added. The warmgranules are returned to the mixer.

[0069] The coated granules are removed from the mixer and allowed tocool. The granules are then passed through a 12-mesh screen. Thegranulate is then lubricated by mixing the required quantity of talc andmagnesium stearate in a suitable blender. Tablets are compressed to 375mg in weight on a suitable tableting machine. The formula for thetablets of Example 1 is set forth in Table 1 below: TABLE 1 Formula ofOxycodone HCl 30-mg Tablets Component mg/Tablet % (by wt) OxycodoneHydrochloride 30.0  8 Lactose (spray-dried) 213.75 57 Eudragit ® RS PM45.0 12 Purified Water q.s* — Stearyl Alcohol 75.0 20 Talc 7.5  2Magnesium Stearate 3.75  1 Total: 375.0 100 

[0070] The tablets of Example 1 are then tested for dissolution via theUSP Basket Method, 37° C., 100 RPM, first hour 700 ml gastric fluid atpH 1.2, then changed to 900 ml at 7.5. The results are set forth inTable 2 below: TABLE 2 Dissolution of Oxycodone 30 mg Controlled ReleaseTablets Time % Oxycodone Dissolved 1 33.1 2 43.5 4 58.2 8 73.2 12 81.818 85.8 24 89.2

EXAMPLE 2 Controlled Oxycodone HCl 10 mg Release Tablets—OrganicManufacture

[0071] The required quantities of oxycodone hydrochloride and spraydried lactose are transferred into an appropriate sized mixer and mixfor approximately 6 minutes. Approximately 40 percent of the requiredEudragit® RS PM powder is dispersed in Ethanol. While the powders aremixing, the powders are granulated with the dispersion and the mixingcontinued until a moist granular mass is formed. Additional ethanol isadded if needed to reach granulation end point. The granulation istransferred to a fluid bed dryer and dried at 30° C.; and then passedthrough a 12-mesh screen. The remaining Eudragit® RS PM is dispersed ina solvent of 90 parts ethanol and 10 parts purified water; and sprayedonto the granules in the fluid bed granulator/dryer at 30° C. Next, thegranulate is passed through a 12-mesh screen. The required quantity ofstearyl alcohol is melted at approximately 60-70° C. The warm granulesare returned to the mixer. While mixing, the melted stearyl alcohol isadded. The coated granules are removed from the mixer and allowed tocool. Thereafter, they are passed through a 12-mesh screen.

[0072] Next, the granulate is lubricated by mixing the requiredquantities of talc and magnesium stearate in a suitable blender. Thegranulate is then compressed to 125 mg tablets on a suitable tabletingmachine.

[0073] The formula for the tablets of Example 2 (10 mg controlledrelease oxycodone) is set forth in Table 3 below: TABLE 3 Formula ofOxycodone HCl 10 mg Controlled Release Tablets Percent ComponentMg/Tablet (by wt) Oxycodone hydrochloride 10.00  8 Lactose (spray-dried)71.25 57 Eudragit ® RS PM 15.00 12 Ethanol q.s.* — Purified Water q.s.*— Stearyl Alcohol 25.00 20 Talc 2.50  2 Magnesium stearate 1.25  1Total: 125.00 mg 100 

[0074] The tablets of Example 2 are then tested for dissolution via USPBasket Method at 37° C., 100 RPM, first hour 700 ml simulated gastric(pH 1.2) then changed to 900 ml at pH 7.5.

[0075] The results are set forth in Table 4 below: TABLE 4 Dissolutionof Oxycodone 10 mg Controlled Release Tablets Hour % Dissolved 1 35.9 247.7 4 58.5 8 67.7 12 74.5 18 76.9 24 81.2

EXAMPLES 3-4 Controlled Release Oxycodone 10 and 20 mg Tablets (AqueousManufacture)

[0076] Eudragit® RS 30D and Triacetin® are combined while passing thougha 60 mesh screen, and mixed under low shear for approximately 5 minutesor until a uniform dispersion is observed.

[0077] Next, suitable quantities of Oxycodone HCl, lactose, and povidoneare placed into a fluid bed granulator/dryer (FBD) bowl, and thesuspension sprayed onto the powder in the fluid bed. After spraying, thegranulation is passed through a #12 screen if necessary to reduce lumps.The dry granulation is placed in a mixer.

[0078] In the meantime, the required amount of stearyl alcohol is meltedat a temperature of approximately 70° C. The melted stearyl alcohol isincorporated into the granulation while mixing. The waxed granulation istransferred to a fluid bed granulator/dryer or trays and allowed to coolto room temperature or below. The cooled granulation is then passedthrough a #12 screen. Thereafter, the waxed granulation is placed in amixer/blender and lubricated with the required amounts of talc andmagnesium stearate for approximately 3 minutes, and then the granulateis compressed into 125 mg tablets on a suitable tableting machine.

[0079] The formula for the tablets of Example 3 is set forth in Table 5below: TABLE 5 Formula of Controlled Release Oxycodone 10 mg TabletsComponent Mg/Tablet % (by wt) Oxycodone Hydrochloride 10.0 8.0 Lactose(spray dried) 69.25 55.4 Povidone 5.0 4.0 Eudragit ® RS 30D (solids)10.0* 8.0 Triacetin ® 2.0 1.6 Stearyl Alcohol 25.0 20.0 Talc 2.5 2.0Magnesium Stearate 1.25 1.0 Total: 125.0 100.0

[0080] The tablets of Example 3 are then tested for dissolution via theUSP Basket Method at 37° C., 100 RPM, first hour 700 ml simulatedgastric fluid at pH 1.2, then changed to 900 ml at pH 7.5. The resultsare set forth in Table 6 below: TABLE 6 Dissolution of Oxycodone 10 mgControlled Release Tablets Hour % Oxycodone Dissolved 1 38.0 2 47.5 462.0 8 79.8 12 91.1 18 94.9 24 98.7

[0081] The formula for the tablets of Example 4 is set forth in Table 7below: TABLE 7 Formula of Controlled Release Oxycodone 20 mg TabletsComponent Mg/Tablet Oxycodone Hydrochloride 20.0 Lactose (spray dried)59.25 Povidone 5.0 Eudragit ® RS 30D (solids) 10.0* Triacetin ® 2.0Stearyl Alcohol 25.0 Talc 2.5 Magnesium Stearate 1.25 Total: 125.0

[0082] The tablets of Example 4 are then tested for dissolution via theUSP Basket Method at 37° C., 100 RPM, first hour 700 ml simulatedgastric fluid at pH 1.2, then changed to 900 ml at pH 7.5. The resultsare set forth in Table a below: TABLE 8 Dissolution of Oxycodone 20 mgControlled Release Tablets Hour % Oxycodone Dissolved 1 31 2 44 4 57 871 12 79 18 86 24 89

EXAMPLES 5-6

[0083] In Example 5, 30 mg controlled release oxycodone hydrochloridetablets are prepared according to the process set forth in Example 1.

[0084] In Example 6, 10 mg controlled release oxycodone hydrochloridetablets are prepared according to the process set forth in Example 2.

[0085] Thereafter, dissolution studies of the tablets of Examples 5 and6 are conducted at different pH levels, namely, pH 1.3, 4.56, 6.88 and7.5.

[0086] The results are provided in Tables 9 and 10 below: TABLE 9Example 5 Percentage Oxycodone HCl 30 mg Tablets Dissolved Over Time pH1 2 4 8 12 18 24 1.3 29.5 43.7 61.8 78.9 91.0 97.0 97.1 4.56 34.4 49.166.4 82.0 95.6 99.4 101.1 6.88 32.8 47.1 64.4 81.9 92.8 100.5 105.0 7.527.0 38.6 53.5 70.0 81.8 89.7 96.6

[0087] TABLE 10 Example 6 Percentage Oxycodone HCl - 10 mg TabletsDissolved Over Time pH 1 2 4 8 12 18 24 1.3 25.9 41.5 58.5 73.5 85.390.7 94.2 4.56 37.8 44.2 59.4 78.6 88.2 91.2 93.7 6.88 34.7 45.2 60.075.5 81.4 90.3 93.9 7.5 33.2 40.1 51.5 66.3 75.2 81.7 86.8

EXAMPLES 7-12

[0088] In Examples 7-12, 4 mg and 10 mg oxycodone HCl tablets wereprepared according to the formulations and methods set forth in theassignee's U.S. Pat. No. 4,990,341.

[0089] In Example 7, oxycodone hydrochloride (10.00 gm) was wetgranulated with lactose monohydrate (417.5 gm) and hydroxyethylcellulose (100.00 gm), and the granules were sieved through a 12 meshscreen. The granules were then dried in a fluid bed dryer at 50° C. andsieved through a 16 mesh screen.

[0090] Molten cetostearyl alcohol (300.0 gm) was added to the warmedoxycodone containing granules, and the whole was mixed thoroughly. Themixture was allowed to cool in the air, regranulated and sieved througha 16 mesh screen.

[0091] Purified Talc (15.0 gm) and magnesium stearate (7.5 gm) were thenadded and mixed with the granules. The granules were then compressedinto tablets.

[0092] Example 8 is prepared in the same manner as Example 0.7; however,the formulation includes 10 mg oxycodone HCl/tablet. The formulas forExamples 7 and 8 are set forth in Tables 11 and 12, respectively. TABLE11 Formulation of Example 7 Ingredient mg/tablet g/batch Oxycodonehydrochloride 4.0 10.0 Lactose monohydrate 167.0 417.5Hydroxyethylcellulose 40.0 100.0 Cetostearyl alcohol 120.0 300.0Purified talc 6.0 15.0 Magnesium stearate 3.0 7.5

[0093] TABLE 12 Formulation of Example 8 Ingredient mg/tablet g/batchOxycodone hydrochloride 10.0 25.0 Lactose monohydrate 167.0 417.5Hydroxyethylcellulose 40.0 100.0 Cetostearyl alcohol 120.0 300.0 Talc6.0 15.0 Magnesium stearate 3.0 7.5

[0094] In Example 9, 4 mg oxycodone HCl controlled release tablets areprepared according to the excipient formula cited in Example 2 of U.S.Pat. No. 4,990,341. The method of manufacture is the same as set forthin Examples 7 and 8 above. Example 10 is prepared according to Example9, except that 10 mg oxycodone HCl is included per tablet. The formulasfor Examples 9 and 10 are set forth in Tables 13 and 14, respectively.TABLE 13 Formulation of Example 9 Ingredient mg/tablet g/batch Oxycodonehydrochloride 4.0 10.0 Anhydrous Lactose 167.0 417.5Hydroxyethylcellulose 30.0 75.0 Cetostearyl alcohol 90.0 225.0 Talc 6.015.0 Magnesium stearate 3.0 7.5

[0095] TABLE 14 Formulation of Example 14 Ingredient mg/tablet g/batchOxycodone hydrochloride 10.0 25.0 Hydrous lactose 167.0 417.5Hydroxyethylcellulose 30.0 75.0 Cetostearyl alcohol 90.0 225.0 Talc 6.015.0 Magnesium stearate 3.0 7.5

[0096] In Example 11, oxycodone 4 mg controlled release tablets areprepared with the same excipient formula cited in Example 3 of U.S. Pat.No. 4,990,341.

[0097] Oxycodone hydrochloride (32.0 gm) was wet granulated with lactosemonohydrate (240.0 gm) hydroxyethyl cellulose (80.0 gm) and methacrylicacid copolymer (240.0 gm, Eudragit® L-100-55), and the granules weresieved through a 12 mesh screen. The granules were then dried in a FluidBed Dryer at 50° C. and passed through a 16 mesh screen.

[0098] The warmed oxycodone containing granules was added moltencetostearyl alcohol (240.0 gm), and the whole was mixed thoroughly. Themixture was allowed to cool in the air, regranulated and sieved througha 16 mesh screen. The granules were then compressed into tablets.

[0099] Example 12 is prepared in identical fashion to Example 11, exceptthat 10 mg oxycodone HCl is included per tablet. The formulations forExamples 11 and 12 are set forth in Tables 15 and 16, respectively.TABLE 15 Formulation of Example 11 Ingredient mg/tablet g/batchOxycodone hydrochloride 4.0 32.0 Lactose monohydrate 30.0 240.5Hydroxyethylcellulose 10.0 80.0 Methacrylic acid copolymer 30.0 240.0Cetostearyl alcohol 30.0 240.0

[0100] TABLE 16 Formulation of Example 12 Ingredient mg/tablet g/batchOxycodone hydrochloride 10.0 80.0 Lactose monohydrate 30.0 240.5Hydroxyethylcellulose 10.0 80.0 Methacrylic acid copolymer 30.0 240.0Cetostearyl alcohol 30.0 240.0

[0101] Next, dissolution studies were conducted on the tablets ofExamples 7-12 using the USP basket method as described in the U.S.Pharmacopoeia XXII (1990). The speed was 100 rpm, the medium wassimulated gastric fluid for the first hour followed by simulatedintestinal fluid thereafter, at a temperature of 37° C. Results aregiven in Table 17. TABLE 17 DISSOLUTION STUDIES OF EXAMPLES 7-12 Time %Oxycodone Dissolved. (hrs) Ex. 7 Ex. 8 Ex. 9 Ex. 10 Ex. 11 Ex. 12 1 23.325.5 28.1 29.3 31.3 40.9 2 35.6 37.5 41.5 43.2 44.9 55.6 4 52.9 56.461.2 63.6 62.1 74.2 8 75.3 79.2 83.7 88.0 82.0 93.9 12 90.7 94.5 95.2100.0 91.4 100.0

EXAMPLES 13-16 Clinical Studies

[0102] In Examples 13-16, randomized crossover bioavailability studieswere conducted employing the formulation of Examples 2 (organicmanufacture) and 3, (aqueous manufacture).

[0103] In Example 13, a single dose fast/fed study was conducted on 24subjects with oxycodone tablets prepared according to Example 3.

[0104] In Example 14, a steady-state study was conducted on 23 subjectsafter 12 hours with oxycodone tablets prepared according to Example 2,and compared to a 5 mg oxycodone immediate-release solution.

[0105] In Example 15, a single dose study was conducted on 22 subjectsusing oxycodone tablets prepared according to Example 3, and compared toa 20 mg oxycodone immediate release solution.

[0106] In Example 16, a 12 subject single-dose study was conducted using3×10 mg oxycodone tablets prepared according to Example 3, and comparedto a 30 mg oxycodone immediate release solution.

[0107] The results of Examples 13-16 are set forth in Table TABLE 18 AUCCmax Tmax Example Dosage ng/ml/hr ng/ml hr 13 10 mg CR Fast 63 6.1 3.810 mg CR Fed 68 7.1 3.6 14 5 mg IR q6h 121 17 1.2 10 mg CR q12h 130 173.2 15 20 mg IR 188 40 1.4 2 × 10 mg CR 197 18 2.6 16 30 mg IR 306 531.2 3 × 10 mg CR 350 35 2.6 30 mg CR 352 36 2.9

EXAMPLE 17 Clinical Studies

[0108] In Example 17, a single dose, double blind, randomized studydetermined the relative analgesic efficacy, the acceptability, andrelative duration of action of an oral administration of controlledrelease oxycodone 10, 20 and 30 mg prepared according to the presentinvention (CR OXY) compared to immediate release oxycodone 15 mg (IROXY)., immediate release oxycodone 10 mg in combination withacetaminophen 650 mg (IR OXY/APAP) and placebo in 180 patients withmoderate or severe pain following abdominal or gynecological surgery.Patients rated their pain intensity and pain relief hourly for up to 2hours postdosing. Treatments were compared using standard scales forpain intensity and relief, and onset and duration of pain relief.

[0109] All active treatments were significantly superior to placebo formany of the hourly measures, and for sum pain intensity differences(SPID) and total pain relief (TOTPAR). A dose response was seen amongthe 3 dose levels of CR OXY for pain relief and peak pain intensitydifference (PID), with CR OXY 20 mg and 30 mg being significantly betterthan the 10 mg dose. IR OXY was significantly superior to CR OXY 10 mgat hr 1 and 2. IR OXY/APAP was significantly superior to the 3 doses ofCR OXY at hr 1, and to CR OXY 10 mg at hrs 2 through 5. Onset time wassignificantly shorter for the IR OXY and IR OXY/APAP treatment groups incomparison to the 3 CR OXY treatments. The distribution functions forduration of relief revealed significantly longer duration of relief forthe three CR OXY doses than for IR OXY and IR OXY/APAP. No seriousadverse experiences were reported. The results are more particularlyreported in Table 19 below. TABLE 19 PATIENT DISPOSITION TREATMENT GROUPIR OXY CR OXY 15 10 20 30 2 mg PLACEBO mg mg mg PERC* TOTAL Enrolled and31 31 30 30 30 30 182 Randomized to Study Treatment Entered the 31 31 3030 30 30 182 Study Treat- ment Phase Completed 31 30 30 30 30 30 181 theStudy Discontinued 0 1 0 0 0 0 1 from the Study Excluded from EfficacyAnalysis Vomited 0 1 0 0 0 0 1 prior to 1 hr post dose Inadvertently 1 00 0 0 0 1 received rescue during study Analysis Population: Evaluablefor 30 30 30 30 30 30 180 Safety and Efficacy Evaluable for 31 31 30 3030 30 182 Safety

[0110] The time-effect curves for pain intensity, pain intensitydifferences and pain relief are shown in FIGS. 1-4. CR OXY 10 mg hadsignificantly (p<0.05) lower pain intensity scores than theplacebo-treated patients at hours 3-11 and lower pain scores than IR OXY15 mg and Percocet® at hour 10. CR OXY 20 mg has significantly (p<0.05)lower pain intensity scores compared to placebo at hours 2-11 andsignificantly (p<0.05) lower pain scores than CR OXY 10 mg, IR OXY 15 mgand Percocet at hours 9-11. CR OXY 30 mg had significantly (p<0.05)lower pain scores than placebo at hours 2-11 and lower pain scores thanCR OXY 10 mg at hours 2, 3, and 5 and lower scores than Percocet® athour 10.

[0111] For hourly pain relief scores categorical and visual analogscales (CAT and VAS), CR OXY 10 mg had significantly (p<0.05) higherpain relief scores than placebo at hours 3-11 and higher relief scoresthan IR OXY and Percocet® at hour 10 (and Percocet® at hour 11). CR OXY20 mg had significantly (p<0.05) higher relief scores than placebo athours 2-12 and higher relief scores than Percocet® at hours 9-12. Inaddition, CR OXY had significantly (p<0.05) higher pain relief than IROXY at hours 10-12. CR OXY 30 mg had significantly (p<0.05) higher painrelief scores than placebo at hours 2-12 and higher scores thanPercocet® at hours 9-12 and IR OXY 15 mg at hour 10.

[0112] Each treatment group was significantly (p<0.05) better thanplacebo with respect to the sum of the pain intensity differences (SPID)and total pain relief (TOTPAR).

[0113] Duration of pain relief as measured by the patient stopwatchmethod showed that CR OXY10 mg, 20 mg and 30, mg had significantly(p<0.05) longer duration of action compared to IR OXY 15 mg and 2tablets Percocet®. In addition, the three controlled-releaseformulations had significantly (p<0.05) longer times to remedication,compared to Percocet®.

[0114] Before remedication, a total of 104 (57%) of patients reported120 adverse experiences. The most common were somnolence, fever,dizziness and headache.

[0115] Based upon the results of this study it is concluded that thecontrolled release oxycodone formulations of the present inventionrelieve moderate to severe postoperative pain, e.g., due to abdominal orgynecological surgery in women. There is a dose response noted in whichplacebo <10 mg<20 mg<30 mg CR OXY following a single dose. Onset ofaction occurred in one hour with peak effects noted from 2 to 5 hoursand a duration of effect from 10 to 12 hours. In the chronic painsituation steady state dosing may prolong this effect. Side effects areexpected and easily managed. Headache may be related to dose. Dizzinessand somnolence were reported.

[0116] IR OXY 15 mg has an intermediate peak effect compared tocontrolled release oxycodone. Its duration of action is shorter (6-8hours). Percocet® is quite effective in terms of onset, peak effect andsafety. The duration of action is 6-8 hours.

[0117] In summary, CR OXY was clearly an effective oral analgesic, witha slower onset but a longer duration of effect than either IR OXY or IROXY/APAP.

EXAMPLE 18 Clinical Studies

[0118] In Example 18, a steady state-crossover trial was conducted in 21normal male subjects comparing

[0119] a. CR OXY 10 mg administered every 12 hours (q12h); and

[0120] b. Roxicodone® oral solution 5 mg (ROX) administered every 60hours (q6h),

[0121] Treatment (b) was the study reference-standard. The average agewas 34 years, height 176 cm and weight 75 kg. No unusual features werenoted about the group.

[0122]FIG. 5 shows the mean plasma oxycodone concentrations for the twoformulations over the 12 hour dosing interval. The results aresummarized in Table 18 in terms of mean values, ratios of mean valuesand 90% confidence intervals.

[0123] As inspection of Table 18 reveals, with one exception, nosignificant differences were detected between the two formulations. Thesingle exception is the mean t_(max) for CR OXY of 3.18 hours which, asexpected for a controlled release formulation, significantly exceededthe ROX mean of 1.38 hours. Mean AUC-based bioavailability, (ROX=100%)was 104.4% with 90% confidence limits of 90.9 to 117.9%. Thus, the FDAspecification of ±20% is met so that the study results support anassertion of equal oxycodone availability. TABLE 20 SUMMARY OFPHARMACOKINETIC PARAMETERS FOR OXYCODONE FOLLOWING A SINGLE DOSE OF CROXY (10 mg q12H) AND ROXICODONE ® ORAL SOLUTION (5 mg q6h) OXY/ROXICODONE ROXI 90% PARAMETER CR OXY SOLUTION (%) CI* C_(max) (ng/mL)ARITH. MEAN (SD) 15.11 15.57 97.08 85.59- (4.69) (4.41) 108.50 GEOMETRICMEAN 14.43 15.01 95.14 C_(min) (ng/mL) ARITH. MEAN (SD) 6.24 6.47 96.4180.15- (2.64) (3.07) 112.74 GEOMETRIC MEAN 5.62 5.83 96.48 t_(max) (hrs)ARITH. MEAN 3.18 1.38 230.17 160.71- (SD) (2.21) (0.71)* 298.71 AUC(0-12 hrs) ARITH. 103.50 99.10 104.44 90.92- MEAN (SD) (40.03) (35.04)117.94 GEOMETRIC 97.06 93.97 103.29 MEAN % Swing ARITH. MEAN 176.36179.0 98.53 62.06- (SD) (139.0) (124.25) 134.92 % Fluctuation ARITH.108.69 117.75 92.22 76.81- MEAN (SD) (38.77) (52.47) 107.57 End PointARITH. −1.86 −1.86 99.97 117.77- MEAN (SD) (2.78) (2.19) 22.23

EXAMPLE 19 Clinical Studies

[0124] In Example 19, twenty-four normal, healthy male subjects wereenrolled in a randomized single-dose two-way crossover study to comparethe plasma oxycodone concentrations obtained after dosing with twocontrolled 45 release oxycodone 10 mg tablets versus 20 mg (20 ml of 5mg/5 ml) of immediate release (IR) oxycodone hydrochloride solution.Twenty-three subjects completed the study and were eligible foranalysis.

[0125] Plasma oxycodone concentrations were determined by a highperformance liquid chromatographic procedure. Arithmetic Mean C_(max),t_(max), AUC, and half-lives calculated from individual plasma oxycodoneconcentration-versus-time data are set forth in Table 21: TABLE 21Reference Test Pharmaco- Product Product 90% kinetic IR Oxycodone CROxycodone Confidence Parameter 20 mg 2 × 10 mg F. (%) Interval C_(max)41.60 18.62 44.75 32.5- (ng/ml) 57.0 t_(max) 1.30 2.62 200.83 169.8-(hours) 232.6 AUC 194.35 199.62 102.71 89.5- (0-36) 115.9 (mg × hr/ml)AUC (0-∞) 194.38 208.93 107.49 92.9- (ng × hr/ml) 121.9 t_(1/2 (elim))3.21 7.98* 249.15 219.0- (hrs) 278.8 t_(1/2 (abs)) 0.35 0.92* 264.17216.0- (hrs) 310.7

[0126] For C_(max), t_(max), t_(1/2(elim)) and t_(1/2(abs)) there werestatistically significant differences between the CR OXY and IR OXY.There were no statistically significant differences between the twotreatments in the extent of absorption [AUC (0,36), AUC (0,∞). The 90%confidence interval for CR OXY relative to IR OXY relative was89.5%-115.9% for AUC (0,36) and 92.9%-121.9% for AUC (0,∞). Based on the90% confidence interval analysis, the controlled-release oxycodontableteequivalent in, extent of absorption (AUC 0,36) to the immediate-releaseoxycodone solution. The controlled-release oxycodone absorption wasslower by approximately 1.3 hours. No statistically significantdifferences were noted between the two treatments with reference toadverse experiences, none of which were considered clinically unusualfor opiates for this type of study.

[0127] The above studies demonstrate a significant dose-responserelationship utilizing the controlled release oxycodone formulations ofthe present invention 115 at dosages of 10, 20 and 30 mg which does notdeviate from parallelism with dose-response slopes for MS Contin insimilarly designed well-controlled analgesic efficacy studies of MS.Contin reported by Kaiko R. S., Van Wagner D., Brown J., et al.,“Controlled-Release Oral Morphine (MS Contin® Tablets, MSC) inPostoperative Pain.”, Pain Suppl., 5:S149.1990, who compared 30, 60, 90,and 120 mg of MS Contin as compared with 10 mg of intramuscular morphineand placebo and Bloomfield, et al., “Analgesic Efficacy and Potency ofTwo Oral Controlled-Release Morphine Preparations”, ClinicalPharmacology & Therapeutics, (in press), who compared 30 and 90 mg of MSContin as compared to 30 and 90 mg of another controlled-release oralmorphine preparation, Oramorph SR 30 mg tablets.

[0128] The examples provided above are not meant to be exclusive. Manyother variations of the present invention would be obvious to thoseskilled in the art, and are contemplated to be within the scope of theappended claims.

What is claimed is:
 1. A controlled release oxycodone formulation fororal administration to human patients, comprising from about 10 mg toabout 160 mg oxycodone, based on the hydrochloride salt, saidformulation providing a mean maximum plasma concentration of oxycodonefrom about 6 to about 240 ng/ml from a mean of about 2 to about 4.5hours after administration, said formulation providing a desiredanalgesic effect for at least about 12 hours.
 2. The controlled releaseoxycodone formulation of claim 1, comprising from about 10 to about 40mg oxycodone based on the hydrochloride salt, said formulation providinga mean maximum plasma concentration of oxycodone from about-6 to about60 ng/ml from a mean of about 2 to about 4.5 hours after administration.3. The controlled release oxycodone formulation of claim 1, comprisingfrom about 40 mg to about 160 mg oxycodone based on the hydrochloridesalt, said formulation providing a mean maximum plasma concentration ofoxycodone from about 60 to about 240 ng/ml from a mean of about. 2 toabout 4.5 hours after administration.
 4. The solid controlled releaseoxycodone formulation of claim 1, comprising oxycodone hydrochloridedispersed in an effective amount of a controlled release matrix selectedfrom the group consisting of hydrophilic polymers, hydrophobic polymers,digestible substituted or unsubstituted hydrocarbons having from about 8to about 50 carbon atoms, polyalkylene glycols, and mixtures of any ofthe foregoing, and a suitable amount of a suitable pharmaceuticaldiluent.
 5. The solid controlled release oxycodone formulation of claim1, comprising: (a) an analgesically effective amount of spheroidscomprising oxycodone or a salt thereof and either a spheronising agentor an acrylic polymer or copolymer, such that the total dosage ofoxycodone in said dosage form is from about 0.10 to about 160 mg basedon the hydrochloride salt; and (b) a film coating on said spheroidswhich controls the release of the oxycodone or oxycodone salt at acontrolled rate in an aqueous medium, wherein said composition providesan in vitro dissolution rate of the dosage form.
 6. The controlledrelease oxycodone formulation of claim 1, comprising a tablet whereinsaid oxycodone is dispersed in a controlled release matrix.
 7. Thecontrolled release oxycodone formulation of claim 1, wherein saidoxycodone is in the form of the hydrochloride salt.
 8. A method forsubstantially reducing the range in daily dosages required to controlpain human patients, comprising administering an oral controlled releasedosage formulation comprising from about 10 to about 160 mg oxycodone ora salt thereof based on the hydrochloride salt which provides a meanmaximum plasma concentration of oxycodone from about 6 to about 240ng/ml from a mean of about 2 to about 4.5 hours after administration. 9.A method for substantially reducing the range in daily dosages requiredto control pain in substantially all human patients, comprisingadministering an oral solid controlled release dosage formulationcomprising from about 10 mg to about 40 mg oxycodone or a salt thereofbased on the hydrochloride salt which provides a mean maximum plasmaconcentration of oxycodone from about 6 to about 60 ng/ml from a mean ofup to about 2 to about 4.5 hours after administration.
 10. A method forsubstantially reducing the range in daily dosages required to controlpain in substantially all human patients, comprising administering anoral solid controlled release dosage formulation comprising from about40 mg to about 160 mg oxycodone or a salt thereof based on thehydrochloride salt which provides a mean maximum plasma concentration0.4 of oxycodone from about 60 to about 240 ng/ml from a mean of up toabout 2 to about 4.5 hours after administration.